Researches In Genetic Risk Factors Of Early-onset Diabetes And Diabetic Nephropathy

Early-onset of type 2 diabetes(T2DM) and type 2 diabetic nephropathy(DN) are both complex diseases with genetic heterogeneity, and the associated gene variants studies from different ethnic groups achieve conflicting results, while the discovery of genetic genes and the illustration of function may contribute to early diagnosis and optimal targeted therapy. This study focused on 1) the association of E23 K and A190 A variations of the KCNJ11 gene with early-onset type 2 diabetes and blood pressure; 2) the relationship between preproghrelin(GHRL) gene Leu72 Met polymorphism and diabetic nephropathy.1) The association of E23 K and A190 A variations of the KCNJ11 gene with early-onset type 2 diabetes and blood pressureConflicting associations between defined KCNJ11 variations and susceptibility to late-onset(>40 years-old) T2 DM have been reported in different ethnic groups. We investigated whether the E23K(Gâ†'A, rs5219) or A190A(Câ†'T, rs5218) variations in KCNJ11 are associated with early-onset T2 DM and blood pressure in the Chinese population. The included subjects consisted of 175 unrelated Chinese patients with early-onset T2DM(age of onset <40 years-old) who receive(ins+, n=57) or do not receive insulin(ins-, n=118), and 182 non-diabetic control subjects. PCR-direct sequencing was performed to genotype E23 K and A190A; the genotypic frequencies and associations with clinical characteristics were analyzed. a) The genotypic frequencies of E23K-GA+AA were higher and A190A-TT was lower in the early-onset T2 DM group, especially the T2DM(ins+) group, compared to the non-diabetic control group(p<0.01 or p<0.05, respectively); b) In non-diabetic subjects, E23K-AA carriers had significantly higher 2 hours plasma glucose and lower 2 hours insulin than E23K-GG carriers(both p<0.05); c) A190A-TT or E23K-GG carriers had higher systolic blood pressure(SBP) than CC or AA carriers in the non-diabetic control and T2 DM groups(both p<0.05); d) In the T2 DM ins+ group, E23K-AA carriers had lower onset age and duration of diabetes and higher BMI than GG carriers, and A190A-TT carriers had higher SBP than CC carriers(all p<0.05). The E23K-GA or AA genotypes may increase the susceptibility to and A190A-TT may protect against early-onset T2 DM, while the A190A-TT or E23K-GG genotypes may increase the risk of hypertension in the Chinese population.2) The relationship between GHRL gene Leu72 Met polymorphism and type 2 diabetic nephropathyThe preproghrelin(GHRL) Leu72 Met polymorphism is associated with obesity, reduced glucose-induced insulin secretion in healthy or diabetic subjects, and reduced serum creatinine(Scr) levels in type 2 diabetes. We evaluated the association of the Leu72 Met polymorphism(Câ†'A rs696217) with measures of insulin sensitivity in nondiabetic control individuals and type 2 diabetics, and whether this variation contributes to the development of diabetic nephropathy in type 2 diabetes. 291 non-diabetic control subjects and 466 patients with type 2 diabetes were recruited, of whom 238 had DN with overt albuminuria(DN group; albuminuric excretion rate [AER]≥300 mg/24 h) and 228 did not have DN, but had diabetes for more than 10 years(non-DN group). Genotyping was performed using a Taq Man PCR assay. a) The Leu/Leu, Leu/Met, and Met/Met genotype frequencies were significantly different between the non-DN and DN groups(p=0.011). b) The frequency of the variant genotypes(Leu/Met, Met/Met) was significantly lower in the DN group than the non-DN group(23.5% vs. 36.0%,p=0.003,OR=0.55[95%CI 0.37-0.82]). c) Met/Met non-diabetic control subjects had lower BMI and Scr levels and higher e GFR level than Leu/Leu or Leu/Met individuals(p<0.01 or p<0.05). d) Leu/Met and Met/Met type 2 diabetics had significantly lower AER and Scr levels and higher e GFR level than Leu/Leu type 2 diabetics(all p<0.001). The GHRL Leu72 Met polymorphism may help to maintain normal renal function and may protect against the development of DN by reducing albuminuria and improving renal function in Chinese patients with type 2 diabetes.